Zilpaterol is a known racemic adrenergic β-2 agonist having the following structure:

The CAS name is trans-(±)-4,5,6,7-tetrahydro-7-hydroxy-6-[(1-methylethyl)amino]-imidazo[4,5,1-jk][1]benzazepin-2(1H)-one.
It is well known that zilpaterol, various zilpaterol derivatives, and various pharmaceutically acceptable salts of zilpaterol and its derivatives may, for example, be used to increase the rate of weight gain, improve feed efficiency (i.e., decrease the amount of feed per amount of weight gain), and/or increase carcass leanness (i.e., increase protein content in carcass soft tissue) in livestock, poultry, and/or fish.
In U.S. Pat. No. 4,900,735, for example, Grandadam describes zootechnical compositions of racemic trans zilpaterol and salts thereof that may be used to increase the weight and meat quality of warm-blooded animals, including cattle, pigs, and poultry. And U.S. Patent Appl. Publ. US2005/0284380 describes use of an ionophore/macrolide/zilpaterol dosing regimen to increase beef production, reduce feed intake while maintaining beef production, and reduce incidences of liver abscess in cattle.
Methods for making zilpaterol and salts thereof are known in the art. For example, in U.S. Pat. No. 4,585,770, Frechet et al. describe compounds (and salts thereof) encompassed by a genus characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-jk][1]-benzazepin-2[H]-one derivatives and pharmaceutically acceptable acid addition salts thereof. The derivatives correspond in structure to the following formula:
                Here, R can be various substituents, and the wavy lines indicate that the bonds to the 6-amino and 7-OH groups have the trans configuration. This genus encompasses racemic trans zilpaterol when R is isopropyl.        
Int'l Patent Appl. Publ. WO 2008/119754 discusses making an acid addition salt of zilpaterol free base by mixing the free base with an inorganic or organic acid using various methods known in the art, and specifically mentions HCl.
U.S. Pat. No. 4,585,770 and Int'l Patent Appl. Publ. WO 2008/119754 also discuss the preparation of zilpaterol hydrochloride by dissolving zilpaterol free base in ethanol, adding ethyl acetate saturated with HCl, vacuum-filtering the product to obtain crude zilpaterol hydrochloride, dissolving the crude zilpaterol hydrochloride in hot methanol, adding ethyl acetate, and then filtering to obtain a final zilpaterol hydrochloride product.                Int'l Patent Appl. Publ. WO 2008/119754 also describes processes for making zilpaterol and salts thereof. In some such processes, for example, zilpaterol is prepared from 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid using the following generic scheme:        

Int'l Patent Appl. Publ. WO 2008/119754 goes on to illustrate such a process wherein the chlorinating agent comprises oxalyl chloride; the Lewis acid comprises AlCl3; the hydrolysis acid following the Friedel-Crafts reaction comprises HCl; the inorganic nitrite comprises NaNO2; the acid used in the oximation comprises HCl; water is added to the oximation product mixture to foster isolation of the oxime product; the base used to form the oxime salt comprises KOH; the catalyst for the first hydrogenation comprises palladium on carbon; the acid used in the formation of the isopropylideneamino compound comprises acetic acid; the catalyst for the second hydrogenation comprises platinum on carbon; and the base and alcohol used to form the zilpaterol free base comprise NaOH and ethanol, respectively:

For some applications, it is desirable for zilpaterol or a salt thereof to be in the form of crystals having one or more characteristics, such as a specific size distribution. For example, U.S. Pat. No. 5,731,028 discusses the desirability of a particular crystal size distribution when crystalline zilpaterol hydrochloride is used with 300-800 μm corn cob supports. In that context, U.S. Pat. No. 5,731,028 discusses the desirability of zilpaterol hydrochloride crystals that are less than 300 μm in size, with the majority being from 50 to 200 μm. U.S. Pat. No. 5,731,028 also discusses a desirability to avoid particle sizes so small that that the particles appear in the form of dust, particularly where there is a possibility that such dust could endanger the environment or irritate or poison a user by penetrating the user's pulmonary alveoli. U.S. Pat. No. 5,731,028 specifically discloses crystalline anhydrous zilpaterol hydrochloride having a crystal size distribution wherein less than 5% of the crystals are less than 15 μm, and at least 95% of the crystals are less than 250 μm.
U.S. Pat. No. 5,731,028 discusses various crystallization processes to obtain a desired zilpaterol hydrochloride crystal size distribution that may, for example, be useful with 300-800 μm corn cob supports. These processes include the following various alternatives:                a) Form a supersaturated solution of zilpaterol hydrochloride in water or aqueous ethanol at a temperature greater than 50° C., cool the supersaturated solution to effect crystallization to zilpaterol hydrochloride monohydrate, further cool the solution to a temperature of less than 20° C. to effect crystallization of zilpaterol hydrochloride trihydrate, and dry the hydrated crystals to form the desired crystalline zilpaterol hydrochloride.        b) Dissolve zilpaterol hydrochloride in a minimum of water at 60-100° C., pour the resulting solution into a saturated solution of zilpaterol hydrochloride in aqueous ethanol, seed the mixture with zilpaterol hydrochloride trihydrate crystals while stirring at a temperature of less than 20° C., and dry the resulting zilpaterol hydrochloride trihydrate crystals to form the desired crystalline zilpaterol hydrochloride.        c) Form a saturated aqueous zilpaterol hydrochloride solution by dissolving anhydrous zilpaterol hydrochloride in water at a temperature of less than 30° C. to spontaneously form zilpaterol hydrochloride crystals, and dry the resulting zilpaterol hydrochloride trihydrate crystals to form the desired crystalline zilpaterol hydrochloride.        
In view of the importance of zilpaterol salts in animal production, there continues to be a need for more cost-effective, greater yielding, and/or more selective processes for making crystalline zilpaterol salts, particularly crystalline zilpaterol hydrochloride. The following disclosure addresses this need.